Natalizumab Treatment for Multiple Sclerosis: How Risk Monitoring Reduced PML Complications in France

Table of Contents

• Background: Understanding PML Risk with Natalizumab
• Study Methods: How the Research Was Conducted
• Key Findings: Detailed Results with All Numbers
• Clinical Implications: What This Means for Patients
• Limitations: What the Study Couldn't Prove
• Recommendations: Actionable Advice for Patients
• Source Information

Background: Understanding PML Risk with Natalizumab

Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection caused by the John Cunningham virus (JCV), which is present in most healthy people without causing problems. However, in people with weakened immune systems, including those taking certain multiple sclerosis (MS) medications, this virus can become active and attack the brain's protective covering, leading to severe neurological damage and potentially death.

Natalizumab (marketed as Tysabri) is a highly effective treatment for multiple sclerosis that works by preventing immune cells from entering the brain and causing inflammation. Since its approval, it has been associated with PML cases, creating a significant treatment dilemma for patients and doctors. Before 2012, three main risk factors were identified: treatment duration beyond 24 months, previous immunosuppressant use, and positive JCV antibody status.

In 2013, France implemented nationwide risk-minimization strategies including routine JCV testing and treatment guidelines based on individual risk profiles. This study aimed to determine whether these measures actually reduced PML incidence among natalizumab users in France.

Study Methods: How the Research Was Conducted

Researchers analyzed data from the French MS registry (OFSEP) collected between April 15, 2007, and December 31, 2016. This comprehensive registry includes information from MS specialist centers and neurologist networks across France, representing more than half of all MS patients in the country.

The study included 6,318 patients who received at least one natalizumab infusion during this period. These patients contributed to what researchers call the "at-risk population." The team identified 45 confirmed PML cases among these patients, excluding cases that were only suspected or not properly confirmed.

Researchers calculated PML incidence rates by dividing the number of PML cases by the total person-years of natalizumab exposure. They used sophisticated statistical models (Poisson regression) to analyze how incidence changed over time, particularly before and after January 2013, when risk-minimization strategies became widely implemented.

The study also surveyed treatment centers about their PML risk management practices, including how often they performed JCV testing and magnetic resonance imaging (MRI) monitoring for patients on natalizumab.

Key Findings: Detailed Results with All Numbers

Among the 6,318 patients studied, 74.1% (4,682 patients) were female, with an average age of 28.5 years at MS onset. Patients received natalizumab for an average of 39.6 months, and 21.7% (1,372 patients) had previously taken immunosuppressant medications.

The researchers documented 45 confirmed PML cases during 22,414 person-years of natalizumab exposure. This translates to an overall incidence rate of 2.00 cases per 1,000 person-years (95% CI, 1.46-2.69).

The most significant finding was the dramatic change in PML incidence trends:

• Before 2013: PML incidence increased by 45.3% each year (IRR, 1.45; 95% CI, 1.15-1.83; P = .001)
• After 2013: PML incidence decreased by 23.0% each year (IRR, 0.77; 95% CI, 0.61-0.97; P = .03)

Additional important findings include:

• Younger patients (under 30 years) had an 80% lower risk of developing PML compared to older patients
• Most PML cases (80%) occurred after two years of treatment
• The highest risk period was during the fourth year of treatment, with 6.1 cases per 1,000 patients (95% CI, 3.2-8.99)
• 17.7% of PML cases (8 patients) developed symptoms after stopping natalizumab, mostly within 6 months
• The mortality rate among PML patients was 24.4% (11 patients)

The survey of treatment centers revealed consistent risk-management practices:

• 97.1% of centers performed JCV testing before starting natalizumab
• 90.9% retested JCV-negative patients every 6 months
• 81.8% performed annual MRI monitoring for JCV-negative patients
• 87.5% increased MRI monitoring frequency for JCV-positive patients

Clinical Implications: What This Means for Patients

This study provides strong evidence that systematic risk management can significantly reduce the danger of PML while allowing patients to benefit from natalizumab's effectiveness. The 23% annual decrease in PML cases after 2013 suggests that JCV testing and appropriate monitoring strategies are working.

For patients considering natalizumab treatment, these findings are reassuring. They demonstrate that with proper monitoring, the risks can be managed effectively. The study also confirms that younger patients have substantially lower PML risk, which may influence treatment decisions for different age groups.

The research supports current guidelines recommending regular JCV testing and MRI monitoring for all natalizumab users. It also validates the practice of more frequent monitoring for patients with positive JCV results or longer treatment durations.

Perhaps most importantly, this study shows that the medical community has developed effective strategies to manage the PML risk associated with one of the most effective MS treatments available, allowing more patients to benefit from natalizumab with greater safety.

Limitations: What the Study Couldn't Prove

While this study provides compelling evidence, it has several limitations. As an observational study, it can show associations but cannot definitively prove that the risk-minimization strategies caused the decrease in PML cases. Other factors could have contributed to the decline.

The study only included data through 2016, though additional PML cases reported in 2017 (5 cases) and 2018 (2 cases) support the continuing downward trend. The researchers excluded these later cases from formal analysis due to incomplete data on the total number of patients treated during those years.

The conditional probability estimates for longer treatment durations (beyond 4 years) have wide confidence intervals because fewer patients remained on treatment that long, mainly those with negative JCV results who have lower PML risk anyway.

Finally, this study was conducted in France, and practices might differ in other countries. However, the risk factors for PML and the principles of risk management are likely similar worldwide.

Recommendations: Actionable Advice for Patients

Based on this research, patients using or considering natalizumab should:

1. Ensure regular JCV testing: Get tested before starting treatment and every 6 months thereafter if initially negative
2. Follow recommended MRI monitoring: Typically annual MRIs for JCV-negative patients, more frequently if JCV-positive
3. Discuss personal risk factors: Review your specific situation with your neurologist, including treatment duration, age, and previous immunosuppressant use
4. Be aware of symptoms: Report any new neurological symptoms promptly, even after stopping treatment
5. Participate in shared decision-making: Work with your healthcare team to balance natalizumab's benefits against your individual PML risk

This study demonstrates that with appropriate monitoring, natalizumab can be used more safely than previously thought. The dramatic reduction in PML cases after implementing systematic risk management suggests that following current guidelines significantly protects patients while allowing access to this effective treatment.

Source Information

Original Article Title: Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France

Authors: Sandra Vukusic, MD; Fabien Rollot, MSc; Romain Casey, PhD; et al

Publication: JAMA Neurology, 2020;77(1):94-102. doi:10.1001/jamaneurol.2019.2670

Note: This patient-friendly article is based on peer-reviewed research originally published in JAMA Neurology. It preserves all significant findings, data points, and conclusions from the scientific study while making the information accessible to patients and caregivers.